Association of the inflammation-related proteome with dementia development at older age: results from a large, prospective, population-based cohort study

Abstract Importance Chronic inflammation is increasingly recognized as a central feature of several forms of dementia. Objective To determine which biomarkers of the inflammation-related proteome are associated with all-cause dementia, Alzheimer’s disease (AD), or vascular dementia (VD). Design Analyses were performed in a case-cohort study design based on an ongoing German population-based cohort study. Setting Serum samples of study participants were collected at baseline (2000-20002), and participants were followed up for 17 years. Information about a dementia diagnosis was collected during follow-up via collection of medical records from general practitioners. Participants Ascertainment of potential dementia development during follow-ups was conducted for 6,284 study participants aged 50-75 years at baseline. Biomarker measurements were performed in a randomly collected sample of 1,435 participants and all incident dementia cases of the rest of the cohort (n=393). Main Outcomes and Measures All-cause dementia, AD and VD were the primary outcomes of this analysis. Results Biomarkers were analyzed in 504 all-cause dementia cases (mean age, 67.0 [SD, 5.1] years; 262 female [52.0%], and 242 male [48.0%]) and 1,278 controls (mean age, 61.9 [standard deviation (SD): 6.5] years; 703 female [55.0%], and 575 male [45.0%]). Among the dementia cases, 163 participants developed AD and 195 VD. After correction for multiple testing, 58 biomarkers were statistically significantly associated with all-cause dementia, 22 with AD, and 33 with VD incidence. All analyses were adjusted for potential confounders. Besides single biomarker associations, we identified four biomarker clusters based on the strongest and independently associated biomarkers CX3CL1, EN-RAGE, LAP TGF-beta-1 and VEGF-A. CX3CL1 (Odds ratio [95%-confidence interval] per 1 standard deviation increase: 1.41 [1.24-1.60]) and EN-RAGE (1.41 [1.25-1.60]) were associated with all-cause dementia incidence, EN-RAGE (1.51 [1.25-1.83]) and LAP TGF-beta-1 (1.46 [1.21-1.76]) with AD incidence, and VEGF-A (1.43 [1.20-1.70]) with VD incidence. All named associations were stronger among APOE e4 negative subjects. Conclusion and Relevance This study shows for the first time that the majority of inflammation-related proteins measured in serum samples (58 of 72 tested (80.6%)) are associated with all-cause dementia incidence. Future studies should not only concentrate on single biomarkers but also the complex relationships in biomarker clusters. Key Points Question Which biomarkers of the inflammatory proteome are risk factors for dementia? Findings After correction for multiple testing, in this large prospective cohort study (n=1,782), 58 of 72 tested (80.6%) inflammation-related proteins were associated with all-cause dementia. Furthermore, 22 and 33 were significantly associated with Alzheimer’s disease and vascular dementia. Due to high inter-correlation, only four biomarkers (CX3CL1, EN-RAGE, LAP TGF-beta-1, VEGF-A) were independently associated with dementia outcomes. Meaning The underlying pathophysiology of dementia development might involve complex inflammatory protein clusters, and the identified biomarkers might be promising new drug targets, early diagnostic markers, or parts of prediction models.